ORCID Profile
0000-0003-2332-2312
Current Organisations
UNSW Sydney
,
Westmead Institute for Medical Research
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Publisher: Springer Science and Business Media LLC
Date: 11-01-2017
DOI: 10.1038/SREP40275
Abstract: Cardiovascular disease is the leading cause of death worldwide and patients with severe symptoms undergo cardiac surgery. Even after uncomplicated surgeries, some patients experience postoperative complications such as lung injury. We hypothesized that the procedure elicits metabolic activity that can be related to the disease progression, which is commonly observed two-three days postoperatively. More than 700 blood s les were collected from 50 patients at nine time points pre-, intra-, and postoperatively. Dramatic metabolite shifts were observed during and immediately after the intervention. Prolonged surgical stress was linked to an augmented anaerobic environment. Time series analysis showed shifts in purine-, nicotinic acid-, tyrosine-, hyaluronic acid-, ketone-, fatty acid, and lipid metabolism. A characteristic ‘metabolic biosignature’ was identified correlating with the risk of developing postoperative complications two days before the first clinical signs of lung injury. Hence, this study demonstrates the link between intra- and postoperative time-dependent metabolite changes and later postoperative outcome. In addition, the results indicate that metabotyping patients’ journeys early, during or just after the end of surgery, may have potential impact in hospitals for the early diagnosis of postoperative lung injury, and for the monitoring of therapeutics targeting disease progression.
Publisher: European Respiratory Society (ERS)
Date: 10-2020
DOI: 10.1183/23120541.00009-2020
Abstract: Exhaled breath condensate (EBC) is safely collected in mechanically ventilated (MV) patients, but there are no guidelines regarding humidification of inhaled air during EBC collection. We investigated the influence of active and passive air humidification on EBC volumes obtained from MV patients. We collected 29 EBC s les from 21 critically ill MV patients with one condition of active humidification and four different conditions of non-humidification 19 s les from 19 surgical MV patients with passive humidification and two s les from artificial lungs MV with active humidification. The main outcome was the obtained EBC volume per 100 L exhaled air. When collected with different conditions of non-humidification, mean [95% CI] EBC volumes did not differ significantly (1.35 [1.23 1.46] versus 1.16 [1.05 1.28] versus 1.27 [1.13 1.41] versus 1.17 [1.00 1.33] mL/100 L, p=0.114). EBC volumes were higher with active humidification than with non-humidification (2.05 [1.91 2.19] versus 1.25 [1.17 1.32] mL/100 L, p .001). The volume difference between these corresponded to the EBC volume obtained from artificial lungs (0.81 [0.62 0.99] versus 0.89 mL/100 L, p=0.287). EBC volumes were lower for surgical MV patients with passive humidification compared to critically ill MV patients with non-humidification (0.55 [0.47 0.63] versus 1.25 [1.17 1.32] mL/100 L, p .001). While active humidification increases EBC volumes, passive humidification decreases EBC volumes and possibly influences EBC composition by other mechanisms. We propose that EBC should be collected from MV patients without air humidification to improve reproducibility and comparability across studies, and that humidification conditions should always be reported.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2020
DOI: 10.1038/S42003-020-01495-Y
Abstract: Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2021
DOI: 10.1038/S41598-021-97969-Y
Abstract: Alzheimer’s disease (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics however, comprehensive plasma profiling is challenging due to the dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood–brain barrier and may provide a source for AD biomarkers. We investigated plasma-derived EV proteins for AD biomarkers from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The ultracentrifuged EVs were washed and confirmed according to the MISEV2018 guidelines. Some AD patients presented with highly elevated FXIIIA1 (log 2 FC: 4.6, p -value: 0.005) and FXIIIB (log 2 FC: 4.9, p -value: 0.018). A panel of proteins was identified discriminating Con from AD (AUC: 0.91, CI: 0.67–1.00) with ORM2 (AUC: 1.00, CI: 1.00–1.00), RBP4 (AUC: 0.99, CI: 0.95–1.00), and HYDIN (AUC: 0.89, CI: 0.72–1.00) were found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible AD biomarkers. Some of the MCI patients, with similar protein profiles as the AD group, progressed to AD within a 2-year timespan.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 03-2016
Publisher: Springer Science and Business Media LLC
Date: 07-01-2022
DOI: 10.1186/S12014-021-09339-5
Abstract: Early detection of small cell lung cancer (SCLC) crucially demands highly reliable markers. Growing evidence suggests that extracellular vesicles carry tumor cell-specific cargo suitable as protein markers in cancer. Quantitative proteomic profiling of circulating microvesicles and exosomes can be a high-throughput platform for discovery of novel molecular insights and putative markers. Hence, this study aimed to investigate proteome dynamics of plasma-derived microvesicles and exosomes in newly diagnosed SCLC patients to improve early detection. Plasma-derived microvesicles and exosomes from 24 healthy controls and 24 SCLC patients were isolated from plasma by either high-speed- or ultracentrifugation. Proteins derived from these extracellular vesicles were quantified using label-free mass spectrometry and statistical analysis was carried out aiming at identifying significantly altered protein expressions between SCLC patients and healthy controls. Furthermore, significantly expressed proteins were subjected to functional enrichment analysis to identify biological pathways implicated in SCLC pathogenesis. Based on fold change (FC) ≥ 2 or ≤ 0.5 and AUC ≥ 0.70 ( p 0.05), we identified 10 common and 16 and 17 unique proteins for microvesicles and exosomes, respectively. Among these proteins, we found dysregulation of coagulation factor XIII A (Log 2 FC = − 1.1, p = 0.0003, AUC = 0.82, 95% CI: 0.69–0.96) and complement factor H-related protein 4 (Log 2 FC = 1.2, p = 0.0005, AUC = 0.82, 95% CI 0.67–0.97) in SCLC patients compared to healthy in iduals. Our data may indicate a novel tumor-suppressing role of blood coagulation and involvement of complement activation in SCLC pathogenesis. In comparing SCLC patients and healthy in iduals, several differentially expressed proteins were identified. This is the first study showing that circulating extracellular vesicles may encompass specific proteins with potential diagnostic attributes for SCLC, thereby opening new opportunities as novel non-invasive markers.
Publisher: Aalborg University Press
Date: 2016
Publisher: MDPI AG
Date: 21-09-2018
Abstract: Pulmonary dysfunction is among the most frequent complications to cardiac surgeries. Exposure of blood to the cardiopulmonary bypass (CPB) circuit with subsequent lung ischemia-reperfusion leads to the production of inflammatory mediators and increases in microvascular permeability. The study aimed to elucidate histological, cellular, and metabolite changes following two lung protective regimens during CPB with Histidine-Tryptophan-Ketoglutarate (HTK) enriched or warm oxygenated blood pulmonary perfusion compared to standard regimen with no pulmonary perfusion. A total of 90 patients undergoing CPB were randomized to receiving HTK, oxygenated blood or standard regimen. Of these, bronchoalveolar lavage fluid (BALF) and lung tissue biopsies were obtained before and after CPB from 47 and 25 patients, respectively. Histopathological scores, BALF cell counts and metabolite screening were assessed. Multivariate and univariate analyses were performed. Profound histological, cellular, and metabolic changes were identified in all patients after CPB. Histological and cellular changes were similar in the three groups however, some metabolite profiles were different in the HTK patients. While all patients presented an increase in inflammatory cells, metabolic acidosis, protease activity and oxidative stress, HTK patients seemed to be protected against severe acidosis, excessive fatty acid oxidation, and inflammation during ischemia-reperfusion. Additional studies are needed to confirm these findings.
Publisher: Wiley
Date: 05-05-2021
DOI: 10.1111/JCMM.16522
Abstract: Carbon monoxide (CO) is the leading cause of death by poisoning worldwide. The aim was to explore the effects of mild and severe poisoning on blood gas parameters and metabolites. Eleven pigs were exposed to CO intoxication and had blood collected before and during poisoning. Mild CO poisoning (carboxyhaemoglobin, COHb 35.2 ± 7.9%) was achieved at 32 ± 13 minutes, and severe poisoning (69.3 ± 10.2% COHb) at 64 ± 23 minutes from baseline (2.9 ± 0.5% COHb). Blood gas parameters and metabolites were measured on a blood gas analyser and nuclear magnetic resonance spectrometer, respectively. Unsupervised principal component, analysis of variance and Pearson's correlation tests were applied. A P ‐value ≤ .05 was considered statistically significant. Mild poisoning resulted in a 28.4% drop in oxyhaemoglobin (OHb) and 12‐fold increase in COHb, while severe poisoning in a 65% drop in OHb and 24‐fold increase in COHb. Among others, metabolites implicated in regulation of metabolic acidosis (lactate, P .0001), energy balance (pyruvate, P .0001 3‐hydroxybutyrc acid, P = .01), respiration (citrate, P = .007 succinate, P = .0003 fumarate, P .0001), lipid metabolism (glycerol, P = .002 choline, P = .0002) and antioxidant‐oxidant balance (glutathione, P = .03 hypoxanthine, P .0001) were altered, especially during severe poisoning. Our study adds new insights into the deranged metabolism of CO poisoning and leads the way for further investigation.
Publisher: Elsevier BV
Date: 12-2019
Publisher: MDPI AG
Date: 07-07-2020
DOI: 10.3390/BIOMEDICINES8070199
Abstract: Easily accessible biomarkers for Alzheimer’s dementia (AD) are lacking and established clinical markers are limited in applicability. Blood is a common biofluid for biomarker discoveries, and extracellular vesicles (EVs) may provide a matrix for exploring AD related biomarkers. Thus, we investigated proteins related to neurological and inflammatory processes in plasma and EVs. By proximity extension assay (PEA), 182 proteins were measured in plasma and EVs from patients with AD (n = 10), Mild Cognitive Impairment (MCI, n = 10), and healthy controls (n = 10). Plasma-derived EVs were enriched by 20,000× g, 1 h, 4 °C, and confirmed using nanoparticle tracking analysis (NTA), western blotting, and transmission electron microscopy with immunolabelling (IEM). Presence of CD9+ EVs was confirmed by western blotting and IEM. No group differences in particle concentration or size were detected by NTA. However, significant protein profiles were observed among subjects, particularly for EVs. Several proteins and their ratios could distinguish cognitively affected from healthy in iduals. For plasma TGF-α│CCL20 (AUC = 0.96, 95% CI = 0.88–1.00, p = 0.001) and EVs CLEC1B│CCL11 (AUC = 0.95, 95% CI = 0.86–1.00, p = 0.001) showed diagnostic capabilities. Using PEA, we identified protein profiles capable of distinguishing healthy controls from AD patients. EVs provided additional biological information related to AD not observed in plasma alone.
Publisher: Springer Science and Business Media LLC
Date: 08-2019
DOI: 10.1007/S11306-019-1569-3
Abstract: Progressive chronic kidney disease (CKD) is an important cause of morbidity and mortality. It has a long asymptomatic phase, where routine blood tests cannot identify early functional losses, and therefore identifying common mechanisms across the many etiologies is an important goal. Our aim was to characterize serum, urine and tissue (kidney, lung, heart, spleen and liver) metabolomics changes in a rat model of CKD. A total of 17 male Wistar rats underwent 5/6 nephrectomy, whilst 13 rats underwent sham operation. Urine s les were collected weekly, for 6 weeks blood was collected at weeks 0, 3 and 6 and tissue s les were collected at week 6. S les were analyzed on a nuclear magnetic resonance spectroscopy platform with multivariate and univariate data analysis. Changes in several metabolites were statistically significant. Allantoin was affected in all compartments. Renal asparagine, creatine, hippurate and trimethylamine were significantly different in other tissues creatine, dimethylamine, dimethylglycine, trigonelline and trimethylamine were significant. Benzoate, citrate, dimethylglycine, fumarate, guanidinoacetate, malate, myo-inositol and oxoglutarate were altered in urine or serum. Although the metabolic picture is complex, we suggest oxidative stress, the gut-kidney axis, acid-base balance, and energy metabolism as promising areas for future investigation.
Publisher: Elsevier BV
Date: 12-2020
Publisher: MDPI AG
Date: 21-11-2018
DOI: 10.3390/JCM7110462
Abstract: Cardiac surgery with cardiopulmonary bypass (CPB) causes an acute lung ischemia-reperfusion injury, which can develop to pulmonary dysfunction postoperatively. This sub-study of the Pulmonary Protection Trial aimed to elucidate changes in arterial blood gas analyses, inflammatory protein interleukin-6, and metabolites of 90 chronic obstructive pulmonary disease patients following two lung protective regimens of pulmonary artery perfusion with either hypothermic histidine-tryptophan-ketoglutarate (HTK) solution or normothermic oxygenated blood during CPB, compared to the standard CPB with no pulmonary perfusion. Blood was collected at six time points before, during, and up to 20 h post-CPB. Blood gas analysis, enzyme-linked immunosorbent assay, and nuclear magnetic resonance spectroscopy were used, and multivariate and univariate statistical analyses were performed. All patients had decreased gas exchange, augmented inflammation, and metabolite alteration during and after CPB. While no difference was observed between patients receiving oxygenated blood and standard CPB, patients receiving HTK solution had an excess of metabolites involved in energy production and detoxification of reactive oxygen species. Also, patients receiving HTK suffered a transient isotonic hyponatremia that resolved within 20 h post-CPB. Additional studies are needed to further elucidate how to diminish lung ischemia-reperfusion injury during CPB, and thereby, reduce the risk of developing severe postoperative pulmonary dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2016
Publisher: Springer Science and Business Media LLC
Date: 24-06-2020
DOI: 10.1038/S41597-020-0545-0
Abstract: Cardiovascular disease is the leading cause of death worldwide and cardiac surgery is a key treatment. This study explores metabolite changes as a consequence of ischemia-reperfusion due to cardiac surgery with the use of cardiopulmonary bypass (CPB). To describe the ischemia-reperfusion injury, metabolite changes were monitored in fifty patients before and after CPB at multiple time points. We describe a longitudinal metabolite dataset containing nearly 600 serum nuclear magnetic resonance (NMR) spectra obtained from s les collected simultaneously from the pulmonary artery (deoxygenated blood) and left atrium (oxygenated blood) before ischemia (pre-CPB), immediately after reperfusion (end-CPB), and the following 2, 4, 8, and 20 hours postoperatively. In addition, a longitudinal dataset including 57 quantified metabolites is also provided. These datasets will help researchers studying ischemia-reperfusion injury, as well as the time-dependent alterations related to the surgical trauma and the subsequent processes required in regaining metabolite balance. The datasets could also be used for the development of processing algorithms for NMR-based metabolomics studies and methods for the analysis of longitudinal multivariate data.
Publisher: Wiley
Date: 2016
DOI: 10.3402/JEV.V5.31242
Abstract: Understanding the pathogenic role of extracellular vesicles (EVs) in disease and their potential diagnostic and therapeutic utility is extremely reliant on in-depth quantification, measurement and identification of EV sub-populations. Quantification of EVs has presented several challenges, predominantly due to the small size of vesicles such as exosomes and the availability of various technologies to measure nanosized particles, each technology having its own limitations. A standardized methodology to measure the concentration of extracellular vesicles (EVs) has been developed and tested. The method is based on measuring the EV concentration as a function of a defined size range. Blood plasma EVs are isolated and purified using size exclusion columns (qEV) and consecutively measured with tunable resistive pulse sensing (TRPS). Six independent research groups measured liposome and EV s les with the aim to evaluate the developed methodology. Each group measured identical s les using up to 5 nanopores with 3 repeat measurements per pore. Descriptive statistics and unsupervised multivariate data analysis with principal component analysis (PCA) were used to evaluate reproducibility across the groups and to explore and visualise possible patterns and outliers in EV and liposome data sets. PCA revealed good reproducibility within and between laboratories, with few minor outlying s les. Measured mean liposome (not filtered with qEV) and EV (filtered with qEV) concentrations had coefficients of variance of 23.9% and 52.5%, respectively. The increased variance of the EV concentration measurements could be attributed to the use of qEVs and the polydisperse nature of EVs. The results of this study demonstrate the feasibility of this standardized methodology to facilitate comparable and reproducible EV concentration measurements.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2016
Publisher: Springer Science and Business Media LLC
Date: 19-12-2019
DOI: 10.1007/S11306-019-1629-8
Abstract: In our metabolomics studies we have noticed that repeated NMR acquisition on the same s le can result in altered metabolite signal intensities. To investigate the reproducibility of repeated NMR acquisition on selected metabolites in serum and plasma from two large human metabolomics studies. Two peak regions for each metabolite were integrated and changes occurring after reacquisition were correlated. Integral changes were generally small, but serum citrate signals decreased significantly in some s les. Several metabolite integrals were not reproducible in some of the repeated spectra. Following established protocols, randomising analysis order and biomarker validation are important.
No related grants have been discovered for Raluca Maltesen.